Process for preparing ergot alkaloids

ABSTRACT

R1 is hydrogen, lower alkyl, allyl or benzyl and -NH-A is a cyclic polypeptide of the type known in ergot peptide alkaloids. lysergic acid halides, obtained by reaction with thionyl chloride, phosgene or oxalyl chloride are reacted with a salt of the polypeptide amine in the presence of an acid binding agent. Many of the above compounds are of known therapeutic value, and can be described as vaso-active and also have activity on the central nervous system. The invention concerns a novel process for the production of a compound of the formula:   IN WHICH X Y IS THE GROUP

waited States Patent [1 1 Stadler et a1.

[451 Aug. 28, 1973 PROCESS FOR PREPARING ERGOT ALKALOIDS [75 Inventors:Paul Stadler, Biel-Benken Baselland;

Albert i-lloimann, Bottmingen, both of Switzerland [73] Assignee: SandozLtd., (A/K/A Sandoz AG),

Basel, Switzerland 22 Filed: July 19, 1972 21 Appl. No.: 273,114

Related US. Application Data [63] Continuation-in-part of Ser. No.27,156, April 9,

1970, abandoned.

[30] Foreign Application Priority Data Apr. 18, 1969 Switzerland 5895/69Sept. 2, 1969 Switzerland 13262/69 [52] US. CL... 260/268 PE, 260/268TR, 260/2855 [51] Int. Cl C07d 43/20 [58] Field of Search 260/268 PE [56] References Cited UNITED STATES PATENTS 3,227,719 1/1966 Hofmann260/268 TR 3,428,639 2/1969 Stadler 260/268 PE 3,666,762 5/1972 Guttmann260/268 PE OTHER PUBLICATIONS Stadler et al., l-Ielv. Chim. Acta.,Vol.52, p. 1549-1564 (1969).

Primary Examiner-Donald G. Daus Attorney-Gerald D. Sharkin, Thomas O.McGovern et al.

[5 7] ABSTRACT The invention concerns a novel process for the productionof a compound of the formula:

in which x y is the group 6 Claims, No Drawings PROCESS FOR PREPARINGERGOT ALKALOIDS This application is a continuation-in-part of U.S. Pat.application Ser. No. 27,156, filed Apr. 9, 1970 now abandoned. Thepresent invention relates to a new proand R is hydrogen, lower alkyl,i.e., alkyl having one to four carbon atoms, e.g., methyl, ethyl,isopropyl and the like, allyl or benzyl and NH-A is a cyclic polypeptideof the ergot alkaloid polypeptide type.

Specific polypeptide radicals are described in respect to some ergotalkaloids in the Examples below. It is to be understood however, thatother peptide groups are also contemplated, in particular thepolypeptide group contained in ergotamine, ergostine, ergocristine,ergovaline, ergocryptine, ergocomine and ergonine. The polypeptidescontemplated normally have the general formula R OH where y R, ishydrogen or lower alkyl as'defined above and R is lower alkyl as definedabove or benzyl.

The process according to this invention comprises the steps of:

a. forming an amido halide by treating in an inert solvent anN-di(lower) alkyl substituted acid amide of the formula CORi R2 iv witha halo'genating agent selected from the group consisting of thionylchloride, phosgene and oxalyl chloride where g R, is hydrogen, methyl orethyl, and

R and R are each independently lower alkyl having one to three carbonatoms;

b. reacting said amido halide with a lysergic acid compound of theformula:

R is as defined above in an inert solvent to form a lysergic acid adductintermediate and c. reacting said lysergic acid adduct intermediate witha salt of an amine of the formula ll where NHA is as defined above in aninert solvent and in the presence of an acid binding agent whichliberates the base of the amine HNH-A from its salt.

One preferred method of carrying out the process of the inventionconsists in that a mixture, consisting of l-R -lysergic acids,l-R,-isolysergic acids and l-R,-6- methyl A -ergolene-8-carboxylicacids, is used as the compound of general formula III. For example, amixture of lysergic acid, isolysergic acid and tS-methyI-M'-ergolene-8-carboxylic acid, obtained by saprophytic cultivation of thefungus strain NRRL 3080 of the species Claviceps paspali Stevens etHall, may be used as compound of general formula III. The compound ofgeneral formula II is employed in the form of a salt, since suchcompounds are normally unstable in free base form. Hydrochloric acid ispreferably used as saltforming acid, although other mineral acids maylikewise be used.

The reaction in accordance with the invention involves as anintermediate an amido halide formed by the action of thionyl chloride,phosgene or oxalyl chloride on a N-di(lower) alkyl-substituted acidamide of formula IV. This amido halide is capable of activating thelysergic acid compounds of general formula III by the formation of anadduct. The activation reaction is independent of the sequence of theaddition of the reagents; and the intermediate formation of the amidohalide and the reactive adduct takes place even if the compounds ofgeneral formula III are added in a mixture of an N-di(lower)alkyl-substituted acid amide of formula IV and an inert solvent, and thehaiogenating agent is subsequently added. The preferred amide of formulaiV is dimethyl formamide.

The acid-binding agent, which causes the liberation of the base ofgeneral formula II from its salts, may likewise be added to the reactionmixture before or after the addition of a salt of a compound of generalformula ll. The acid binding agent can be any organic base capable offreeing the amine II from its salts such as triethylamine, pyridine andthe like, especially pyridine.

Examples of suitable inert organic solvents for the process of theinvention are acetonitrile, chloroform, methylene chloride, an excess ofdimethyl formamide, or mixture thereof.

The reaction may be effected at a temperature between and +C and thereaction period can range between A and 24 hours. After the reaction iscomplete, the final product is isolated from the reaction solution andpurified in manner known per se.

A suitable ratio of the starting materials, i.e. of the amine of formulaII and the lysergic acid compounds of formula III,is 1.5 to 2 mols ofthe lysergic acid compound per mol of the amine in the form of itssalts. The molar ratio of halogenating agent to lysergic acid compoundis preferably about I to about 1.25; and at least 1 mole of N-di(lower)alkyl substituted amide of formula IV per mole of halogenating agent isrequired to form the amido-halide intermediate, although it is preferredthat the reaction be carried out using a molar excess of amide IV.

After the reaction is complete, the reaction mixture is worked up inmanner known per se.

An advantage of the process of the invention, as compared with the knownreaction of an acid chloride hydrochloride of the lysergic acid serieswith a salt of the basic peptide portion of ergot alkaloids, in an inertorganic solvent and in the presence of an acid-binding agent, consistsin that the production and isolation of the chloride hydrochloride ofthe lysergic acid series are here avoided.

In the case of the production of the acid chloride hydrochlorides of thelysergic acid series it is necessary to use a large excess of purephosphorous trichloride and phosphorus pentachloride. The destruction ofthis excess after completion of the reaction is a problem, Furthennore,the acid chloride hydrochlorides of the lysergic acid series can only behandled on a technical scale with difficulty, due to their extemehygroscopicity and liability to decomposition. In accordance with theprocess of the present invention such disadvantages are eliminated;furthermore the synthesis of ergot peptide alkaloids is shortened by onestage.

The use of compounds of general formula ill in the form of a mixture oflysergic acid, isolysergic acid and tS-methyl-A -ergolene-carboxylicacid as starting material, has been found to be specially advantageous.This mixture may be obtained directly by saprophytic cultivation of thefungus strain NRRL 3080 of the species Claviceps paspali Stevens etHall. The factors indicated above show that the process of the inventionpermits the production of the pharmacologically highly effectivecompounds of general formula I, e.g., the alkaloids of the ergotamineand the ergotoxin group, using technically readily obtainable andconsiderably less expensive starting materials than those hitherto used.This results in a considerably lowering of production costs for theproducts of the process in accordance with the present invention.

Compounds] are known, and many specific members thereof are of knowntherapeutic value. In general compounds I can be described asvaso-active and also have activity on the central nervous system.Particulars on the activity and use of compounds of known therapeuticvalue are available in the literature.

In the following non-limitative Examples all temperatures are indicatedin degrees Centigrade and are corrected.

EXAMPLE I: ERGOTAMINE AND ERGOTAMININE.

A solution of 3.18 g (25 millimols) of oxalyl chloride in 20 cc ofabsolute acetonitrile is added dropwise during the course of 5 minuteswhile stirring vigorously to 40 cc of absolute dimethyl formamide cooledto l0- and the resulting crystal mass is stirred at the indicatedtemperature for 10 minutes. 5.36 g (20 millimols) of an anhydrousmixture of 40 percent 6-methyl-A ergolene-8-carboxylic acid, 40 percentlysergic acid and 20 percent isolysergic acid are subsequently added,and the resulting dark brown suspension is stirred at about -l0 for afurther 5 minutes. 40 cc of absolute pyridine are then allowed to flowinto the mixture while cooling well, at such a rate that the temperaturedoes not exceed l0. A suspension of 3.68 g (10 millimols) of(2R,SS,l0aS,l0bS)-2-amino-5-benzyl-3,6-dioxo- IOb-hydroxy-2-methyloctahydro-8H-oxazolo[ 3 ,2-a] pyrrolo[2,1-c]-pyrazine hydrochloride in 40 cc of absolute dimethyl formamideis then added, and the reaction mixture is stirred for 2 hours at atemperature between l0' and 0. Working up is effected by diluting with500 cc of methylene chloride and shaking thoroughly with 200 cc of a 2 Nsodium carbonate solution. The aqueous phase is extracted thrice with300 cc of methylene chloride. After drying the combined organicsolutions over sodium sulphate and removing the solvent by distillationin a vacuum, the remaining pyridine is removed by the addition of two200 cc portions of toluene and subsequent distillation. The residueobtained as light ocher-coloured powder is crystallized from 50 cc ofmethanol, whereby pure crystalline ergotaminine, having a M.P. of 236237(decomp), [r 3715 (6 05 in chloroform), is obtained.

The mother liquor is evaporated to dryness, and ergotamine iscrystallized as difficultly soluble sulphate by taking up in a mixtureof 40 cc of methanol and 7 cc of glacial acetic acid with the additionof 0.25 g of sulphuric acid in a small amount of methanol. Afterallowing to stand in a refrigerator for 2 hours, a precipitate of brown,lustrous crystals, having a M.P. of 20l203, is obtained; thisprecipitate is shaken out between 5 percent aqueous ammonia andchloroform, and after drying over sodium sulphate and active charcoal,adding the theoretic amount of d-tartaric acid in methanol andsubsequently concentrating by evaporation, directly yields an almostpure white ergotamine tartrate without further purification.

The mother liquor of the ergotamine sulphate crystallization isconcentrated by evaporation in a vacuum and worked up to a base asdescribed above. Chromatography on a 30-fold quantity of aluminiumoxide, activity I, using methylene chloride as eluant, yields a furtheramount of pure ergotaminine, and elution with methylene chloridecontaining 0.5 percent of methanol yields a further amount ofergotamine. Ergotaminine may be rearranged to ergotamine sulphate bydissolving in a twofold quantity of glacial acetic acid and adding thetheoretic amount of sulphuric acid in a tenfold quantity of methanol, bysimply allowing to stand atroom temperature, whereby the yield of pureergotamine tartrate is correspondingly increased.

EXAMPLE 2: ERGOSTIN E.

Ergostine is obtained in accordance with the process described inExample 1, using 3.18 g (25 millimols) of oxalyl chloride, 5.36 g (20millimols) of an anhydrous mixture of 40 percent 6-methyl-A -ergolene-8-carboxylic acid, 40 percent lysergic acid and 20 percent isolysergicacid and 5.56 g (10 millimols) of (2R,-5S,lOaS,lObS)2-amino-2-ethyl-5-benzyl-3,6-dioxo- IOb-hydroxy-octahydro-8H-oxazolo 3 ,2- a]pyrrolo[2,l-c]pyrazine hydrochloride,2 dioxane.

EXAMPLE 3: ERGOCRISTINE.

Ergocristine is obtained in accordance with the process described inExample 1, using 3.18 g (25 millimols) of oxalyl chloride, 5.36 g (20millimols) of an anhydrous mixture of 40 percent 6-methyl-A--ergolene-8-carboxylic acid, 40 percent lysergic acid and 20 percentisolysergic acid and 4.7 g l millimols) of(2R,5S,l0aS,l0bS)-2-amino-5-benzyl-3,6-dioxolOb-hydroxy-2-isopropyloctahydro-8H-oxazolo[3,2- a]pyrrolo[2,l-c]pyrazine hydrochloride dimethyl formamide.

EXAMPLE 4: ERGOVALINE.

Ergovaline is obtained in accordance with the process described inExample 1, using 3.18 g (25 millimols) of oxalyl chloride, 5.36 g (20millimols) of an anhydrous mixture of 40 percent 6-methyl-A'-ergolene-8-carboxylic acid, 40 percent lysergic acid and 20 percentisolysergic acid and 3.2 g l0 millimols) of 2-amino-2 methylisopropyll0b-hydroxy-3 ,6- dioxo-octahydro-oxazolo[ 3 ,2-a]pyrrola-[ 2, lc]pyrazine hydrochloride.

Ergocomine, ergocryptine and ergonine may be produced in a manneranalogous to the processes described in Examples 1 to 4.

EXAMPLE 5: ERGOTAMINE AND ERGOTAMININE.

A mixture of 10 cc of absolute dimethyl formamide and 30 cc of absolutemethylene chloride is cooled to 10, and a solution of 2.14 g of thionylchloride in 10 cc of methylene chloride is added dropwise. 4.02 g ofhigh vacuum dried d-lysergic acid are subsequently added at 10, and themixture is stirred at 10 for 5 minutes. 3.68 g of2-amino-2-methyl-5-benzyl-lObhyd roxy-3 ,6-dioxo-oxtahydro-oxazolo[ 3,2- a]pyrrolo[2,l-c]pyrazine hydrochloride are subsequently added, andimmediately thereafter 10 cc of absolute pyridine are added dropwise at-10 during the course of minutes while stirring. The reaction mixture isthen stirred in the dark, first at 0 for half an hour and subsequentlyat room temperature for 1%0 hours. Working up is effected by dilutingwith 500 cc of methylene chloride and extracting this solution with 250cc of a 4 N aqueous potash solution. The aqueous phase is extractedthrice with 500 cc amounts of methylene chloride, the methylene chloridesolution is washed with a dilute common salt solution, dried with sodiumsulphate, and the solvent is removed, whereby a brown crude mixture ofbases is obtained, which upon crystallization from 40 cc of methanolyields crude ergotaminine having a MP. of 225-227 (decomp.). Furthercrystallization of this crude crystalline product from methylenechrloide/methanol yields pure ergotaminine having a MP. of 231(decomp.), [01],, +375 (c 0.5 in chloroform).

The mother liquor of the crystallization of the ergotaminine crudecrystalline product is filtered with suction until dry, is dissolved ina small amount of aqueous acetone, and seeding is effected, wherebyergotamine crystallizes in the form of characteristic crystals. MP.l72l75 (decomp.), [11],," =7.7 (c l in pyridine).

EXAMPLE 6: l-METHYL-ERGOTAMINE AND l-METHYL-ERGOTAMININE.

5.95 g of thionyl chloride are added dropwise while stirring during thecourse of 5 minutes to a solution cooled to 10 of 50 cc of absolutedimethyl formamide in 150 cc of absolute methylene chloride, and themixture is stirred for a further 5 minutes. 14.1 g ofl-methyl-d-lysergic acid are subsequently added at 10", and the mixtureis stirred for a further 5 minutes. 30 cc of absolute pyridine are thenadded dropwise at 10 with stirring during the course of 5 minutes to thebrown-coloured solution immediately followed by 9.2 g of2-amino-2-methyl-5benzyl-l0b-hydroxy-3,6- dioxo-octachydro-oxazolo[ 3,2-a ]pyrrolo[ 2,1 c]pyrazine hydrochloride. The reaction mixture isstirred for a further half hour at 0 and then at room temperature for 3hours. Working up is effected by diluting with 700 cc of ethyl acetateand extracting with 500 cc of a 20 percent potash solution. Afterextracting the potash solution thrice with 700 cc amounts of ethylacetate, the ethyl acetate solutions are washed with a common saltsolution, dried with sodium sulphate, and the solvent is removed in avacuum. The residue is chromatographed on 500 g of aluminium oxide,activity 1. l-Methyl-ergotaminine is eluted with methylene chloridecontaining 0.1 percent of methanol, and after crystallization frommethylene chloride/methanol the compound is obtained in pure form. M.P.2l9-220 (decomp.), [11],, +390 (c 0.5 in pyridine). l- Methylergotamineis washed from the column with methylene chloride and 0.2 percent ofmethanol and is purified by crystallization from methylenechloride/methanol. M.P. l67-170 (decomp). [01],, -l63 (c 0.5 inchloroform).

EXAMPLE 7: 9,10-DIHYDRO-ERGOTAMINE.

10.8 g (40 millimols) of 9,10-dihydrolysergic acid are suspended in ccof absolute dimethyl fonnamide, and the suspension is cooled to 10".4.72 g (40 millimols) of thionyl chloride are then added dropwise duringthe course of 5 minutes, and the reaction mixture is stirred at atemperature between 5 and 0 for 30 minutes. After the addition of 40 ccof absolute pyridine at 15 while stirring vigorously, 7.36 g (20millimols) of 2-amino-2-methyl-5-benzyl-l0b-hydroxy- 3,6-dioxo-octahydro-oxazolo[ 3 ,2-a]pyrrolo[ 2, l -c] pyrazinehydrochloride are added, and the resulting brick-red coloured slurry isstirred at 5 to 0 for a further 100 minutes, whereby the reactionmixture turns honey-yellow coloured.

Working up is effected by diluting with 500 cc of chloroform, shakingwith 300 cc of a 2 N ammonia solution and extracting the aqueous phasethrice with 200 cc of chloroform containing 5 percent of methanol. Afterwashing the combined organic phases with water, drying over sodiumsulphate and removing the solvent in a vacuum, a yellow foam isobtained, which after drying in a high vacuum at 100 for 2 hours yieldspure, crystalline 9,10-dihydroergotamine from 60 cc of 90 percentaqueous acetone; after drying at 100 in a high vacuum for 2 hours thecompound has a M.P. of 235 239 (decomp.). [a],," 64 (c l in pyridine).

EXAMPLE 8: 9,lO-DIHYRDO-ERGOCRYPINE.

10.8 g (40 millimols) of 9,10-dihydrolysergic acid are suspended in 100cc of absolute dimethyl formamide, and the suspension is cooled to l.4.72 g (40 millimols) of thionyl chloride are then added dropwise duringthe course of minutes, and the reaction mixture is stirred at atemperature between 5 and 0 for a further 30 minutes. After the additionof 40 cc of absolute pyridine at 15 while stirring vigorously, 7.24 g(20 millimols) of2-amino-2-isopropyl-5-isobutyllOb-hydroxy-3,6-dioxo-octahydro-oxaz010{ 3,2-a]- pyrrolo[2,l-c]pyrazine hydrochloride are added, and the resultingbrick-red coloured slurry is stirred at 5 to 0 for a further 100minutes, whereby the reaction mixture turns honey-yellow coloured.

Working up is effected by diluting with 500 cc of chloroform, shakingwith 300 cc of a 2 N ammonia solution and extracting the aqueous phasethrice with 200 cc of chloroform containing 5 percent of methanol. Afterwashing the combined organic phases with water, drying over sodiumsulphate and removing the solvent in a vacuum, a yellow foam isobtained, which after drying in a high vacuum at 100 for 2 hours yieldspure, crystalline 9,10-dihydro-ergocryptine from 60 cc of ethyl alcohol;after drying at 100 in a high vacuum for 2 hours the compound has a M.P.of 230235 (decomp.). [a] 4l (c l in pyridine).

EXAMPLE 9: 9,lO-DlHYDRO-ERGOCRISTINE.

10.8 g (40 millimols) of 9,10-dihydrolysergic acid are suspended in 100cc of absolute dimethyl formamide, and the suspension is cooled to 10.4.72 g (40 millimols) of thionyl chloride are then added dropwise duringthe course of 5 minutes, and the reaction mixture is stirred at atemperature between 5 and 0 for a further 30 minutes. After the additionof 40 cc of absolute pyridine at while stirring vigorously, 7.96-

g millimols) of 2-amino-2-isopropyl-S-benzyl-lObhydroxy-3,6-dioxo-octahydro-oxazolo[3,2-a1-pyrrolo[2,l-c]pyrazine hydrochloride are added, and the resultingbrick-red coloured slurry is stirred at 5 to 0 for a further 100minutes, whereby the reaction mixture turns honey-yellow coloured.

Working up is effected by diluting with 500 cc of chloroform, shakingwith 300 cc of a 2 N ammonia solution and extracting the aqueous phasethrice with 200 cc of chloroform containing 5 percent of methanol. Afterwashing the combined organic phases with water, drying over sodiumsulphate and removing the solvent in a vacuum, a yellow foam isobtained, which after drying in a high vacuum at 100 for 2 hours yieldspure, crystalline 9,10-dihydro-ergocristine from 60 cc of acetone; afterdrying in a high vacuum at 100 for 2 hours .8 the compound has a M.P. ofl78-l80 (decomp). 01],, (0 l in pyridine.

What is claimed is: I. A process for the production of a compound offormula:

and

R, is hydrogen, lower alkyl, allyl or benzyl and NH-A is a cyclicpolypeptide of the ergot alkaloid polypeptide type which comprises thesteps of:

a. forming an amido halide by treating in an inert solvent anN-di-(lower) alkyl substituted acid amide of the formula and R1 is asdefined above in an inert solvent to form a lysergic acid adductintermediate and c. reacting said lysergic acid adduct intermediate witha salt of an amine of the formula where NHA is defined above in an inertsolvent and in the presence of an acid binding agent which liberates thebase of the amine H-NH-A from its salt.

2. A process according to Claim 1, wherein the lysergic acid compound isa mixure consisting of l-R

2. A process according to Claim 1, wherein the lysergic acid compound isa mixure consisting of 1-R1-lysergic acids, 1-R1-isolysergic acids and1-R1-6-methyl- Delta 8,9 -ergolene-8-carboxylic acids, where R1 is asdefined in claim
 1. 3. A process according to claim 1 in which theN-di-(lower)alkyl-substituted acid amide is dimethyl formamide.
 4. Aprocess according to claim 1, wherein the inert organic solvent isacetonitrile, chloroform, methylene chloride or an excess of dimethylformamide or mixtures thereof.
 5. A process according to claim 1,wherein the acid-binding agent is pyridine.
 6. A process according toclaim 1, wherein the reaction is carried out at a temperature of between-10* and +20*C.